4-(2-hydroxy-3-aminopropoxy)oxindole derivatives

ABSTRACT

The present invention concerns substituted oxindoles of the formula:   WHEREIN R1 is hydrogen or alkyl, both groups R2 are the same and are each hydrogen or alkyl, N IS AN INTEGER FROM 1 TO 8, AND R3 and R4, which are the same or different, are each hydrogen or a carbonyl containing group USEFUL, INTER ALIA, IN THE TREATMENT OF Angina pectoris and heart rhythm disorders.

United States Patent [1 1 Seemann May 6,1975

[ 4-( Z-HYDROXY-3-AMINOPROPOXY)OXIN- DOLE DERIVATIVES [57] ABSTRACT Thepresent invention concerns substituted oxindoles of the formula:

[22] Filed: Dec. 19, 1972 21 A l. N 316,580 1 PP 0 P on 1'2 L I --1+-o--cn -CIH-CH -'Y&Z-C" (ca, -OR

2 2 z n 4 I l/ I [52] US. Cl 260/325 R; 424/274; 260/240 D; wherein260/295 B R is hydrogen or alkyl, both groups [51] Int. Cl C07d 27/40 Re th same and are each hydrogen or alkyl, [58] Field of Search 260/325,240 D, 295 B n i an integer from 1 to 8, and

R and R which are the same or different, are each [56] References Citedhydrogen or a carbonyl containing group UNITED STATES PATENTS useful,inter alia, in the treatment of Angina pectoris 3,696,121 10/1972Troxler 260/326.l5 afid heart rhythm disorders- Primary Examiner-JosephA. Narcavage Attorney, Agent, or FirmGerald D. Sharkin; Robert S. Honor;Thomas O. McGovern 9 Claims, No Drawings 14-(2-HYDROXY-3-AMINOPROPOXY)OXINDOLE DERIVATIVES The present inventionrelates to new heterocyclic compounds and more specifically tosubstituted oxindoles.

In accordance with the invention there are provided new compounds offormula I,

wherein the aminopropoxy side chain is in the 4 or 7 position of theoxindole structure,

R, is hydrogen or alkyl of l to 4 carbon atoms, both groups R are thesame and are each hydrogen or alkyl of l to 4 carbon atoms,

:1 is an integer from l to 8, and

R and R,, which are the same or different, are each hydrogen or thegroup COR wherein R is alkyl of l to [2 carbon atoms; cycloalkyl of 3 to6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms substituted by alkylof l to 4 carbon atoms; a S- or 6-membered heterocycle having a heteroatom selected from oxygen, nitrogen or sulphur; phenyl', phenylalkyl of7 to l2 carbon atoms; styryl', or phenyl, phenylalkyl of 7 to 12 carbonatoms or styryl substituted, on the phenyl nucleus thereof, by fluorine,chlorine, bromine, alkyl of l to 4 carbon atoms or alkoxy of l to 4carbon atoms.

When R is alkyl, this is preferably methyl.

The preferred compounds are those wherein R is hydrogen.

When each R is alkyl, this preferably contains l to 2 carbon atoms andmore preferably is methyl.

The symbol n is preferably an integer from I to 3, more preferably I.

When the radical R is branched alkyl, this is preferably symmetricallybranched at the a carbon atom. In addition, when R is alkyl, thispreferably contains 3 to 10 carbon atoms. Examples are tert.butyl,n-nonyl and n-hexyl. The preferred alkyl radicals are those branched atthe a carbon atom and containing 3 to 6 carbon atoms, e.g., isopropyl,tert.butyl or l,ldimethylpropyl. The tert.butyl group is speciallypreferred.

When R is alkyl substituted cycloalkyl, the alkyl sub stituent ispreferably methyl. The preferred alkyl substituted cycloalkyl ismonoalkylated cycloalkyl, especially monomethylated in the l position. Atypical representative of this series is l-methylcyclohexyl.

When R is a 5- or 6-membered heterocycle, this may be, for example,thienyl, fury], pyridyl or tetrahydropyranyl.

When R is phenylalkyl, this preferably contains up to [0 carbon atoms.An example of this group is the benzyl group. i

o tfimcn cq .a 11

wherein the epoxypropoxy side chain is in the 4 or 7 position of theoxindole structure, and

R is as defined above,

with a compound of formula III,

III 25 il N 'C" (CH -OH wherein n and R are as defined above, to obtaina compound of formula la,

--rm-c-- (cu Ia wherein the aminopropoxy side chain is in the 4 or 7position of the oxindole structure, and

R,, R and n are as defined above,

b. reducing a compound of formula IV,

wherein the aminopropoxy side chain is in the 4 or 7 position of theoxindole structure,

R,, R and n are as defined above, and R is alkyl, preferably of l to 4carbon atoms, e.g. l or 2 carbons, to obtain a compound of formula la,or c. converting a compound of formula Ia into a compound of formula lb,

wherein the aminopropoxy side chain is in the 4 or 7 position of theoxindole structure, one of R' and R, is COR wherein R is as definedabove, and the other is hydrogen, or both R' and R' are COR wherein R isas defined above, by monoor diacylation.

The compounds of formula I may exist either in free base or acidaddition salt forms. Acid addition salt forms may be produced in knownmanner from the free base forms and vice versa.

The reaction in accordance with the invention, of a compound of formulall with a compound of formula III, may be effected in accordance withknown methods. For example, the reaction may be effected in an inertorganic solvent, e.g.. in an aromatic hydrocarbon such as benzene,toluene or xylene, in an ether such as dioxane or tetrahydrofuran, or inamyl alcohol.

The reaction temperature may range e.g., between about and l50C; thereaction is preferably effected at the boiling temperature of thereaction mixture at reflux. The reaction time depends on the reactiontemperature,

The acylation of a compound of formula la may be effected in accordancewith known methods. e.g., by reaction with a halide or anhydride of anacid R COOH, wherein R is as defined above. Either predominantlymonoesters or diesters of compounds of formula la (hereinafter namedmonoor diesters) are obtained depending on the amount of acylating agentused.

The monoesters may be produced by treating the compounds of formula lawith about 1 mol of an acylating agent and conveniently effecting thereaction under mild conditions, preferably at room temperature. Amixture of compounds of formula In which are esterified on the primary(terminal) alcohol group, with compounds which are esterified on thesecondary alcohol group of the aminopropoxy radical, as well asdiesters, is obtained. The separation of these compounds may be effectedin accordance with known methods, e.g.. chromatographically.

The diesters may be produced by treating the com pounds of formula lu,conveniently with an excess of about 2 to 5 mols or more of an acylatingagent, preferably at room temperature.

For example, this may be effected by adding an excess of an acid R COOHto a compound of formula la and adding, in excess if necessary, thecorresponding anhydride to the resulting reaction mixture, depending onthe desired final compounds.

lfdesired, the reaction may be effected in an inert organic solvent,e.g., hexametapol, a chlorinated aliphatic hydrocarbon such aschloroform or a cyclic or open chain ether such as dioxane.

The reaction temperature may range between room temperature and about100C; room temperature is preferably used, as mentioned above, for theproduc tion of the monoester.

After stirring, e.g.. for several hours, the reaction mixture may beworked up, e.g., by pouring the same on ice, making it alkaline with lyeor ammonia and extracting with a water-immiscible inert organic solvent,e.g., ethyl acetate. a cyclic or open chain ether, such as diethylether, or a chlorinated aliphatic hydrocarbon, such as methylenechloride.

The working up stage should naturally be effected under mild conditions,since otherwise the ester groups may be split.

The addition of R COOH may be omitted when the compounds of formula laare used in the form of an acid addition salt with a suitable mineralacid, e.g., hydrochloric acid. The danger of an N-acylation iseliminated by the protonization of the amino group of the aminopropoxyside chain; however, protonization is not essential, especially when Ris alkyl. When the reaction is effected in the presence, e.g., ofhydrogen chloride, the monoor diesters crystallize as hydrochloride andit is not necessary to work up the reaction mixture.

The acylation may naturally likewise be effected with acid halides. Inthis case the reaction is preferably effected at room temperature or ata slightly elevated temperature.

The reduction of compounds of formula IV may be effected in accordancewith known methods for analo gous compounds. Suitable reducing agentsare those which permit the selective reduction of an ester group, i.e.,without affecting the lactam group contained in the oxindole structure.Examples of suitable reducing agents are complex borohydrides such aslithium borohydride.

The reduction of compounds of formula IV, e.g., with lithiumborohydride, may be effected in the usual or ganic solvents for suchreductions, e.g., in an ether such as tetrahydrofuran. The reductionwith lithium borohydride is preferably effected at an elevatedtemperature and in the absence of oxygen.

The production of compounds of formula IV may be effected in a manneranalogous to the processes described for the production of compounds offormula la, by reaction of aminocarboxylic acid esters withepoxypropoxyoxindoles of formula ll.

Compounds of formula ll may be obtained by react ing the correspondinghydroxyoxindole with an epihalohydrin, e.g., epichlorhydrin.

Insofar as the production of the required starting materials is notparticularly described, these are known or may be produced in accordancewith known processes, or in a manner analogous to the processesdescribed herein or to known processes.

The compounds of formula I are useful because they possesspharmacological activity in animals. ln particular, the compounds areuseful as adrenergic B-blocking agents, e.g., in the prophylaxis andtherapy of coronary diseases, particularly in the treatment of Anginapectoris, the hyperkinetic heart syndrome and conditions resulting frommuscular hypertrophic subvalvular aortostenosis, and also asantiarrhythmic agents, e.g., in the treatment of heart rhythm disorders,as indicated in standard tests, e.g., by an inhibition of the positiveinotropic adrenalin effect in the spontaneously beating guinea pigatrium at a bath concentration of from 0.005 to 3 mg/litre, and aprolonged inhibition of the tachycardia and hypotension caused byisoproterenol l- (3,4-dihydroxyphenyl)-Z-isopropylaminoethanol] in theinfusion test in the anaesthetized dog at an effective cumulative dose.administered intravenously by infusion, of from 0.01 to 1 mg/kg animalbody weight.

For the above-mentioned uses, the dosage adminis 5 tered will, ofcourse, vary depending on the compound employed, mode of administrationand treatment de sired. However, in general, satisfactory results areobtained when administered, e.g. orally or parenterally. at

a daily dosage of from about 0.01 to 10 mg/kg animal body weight, whichmay. if necessary, be administered in divided form twice daily. For thelarger mammals, the total daily dosage is in the range of from about 1to 500 mg, and dosage forms suitable for oral administration comprisefrom about 0.5 to 250 mg of the compound, admixed with a solid or liquidpharmaceutical carrier or diluent.

The compounds of formula 1 may be employed in the form of appropriatepharmaceutical compositions including pharmaceutical carriers ordiluents. A suitable form of composition for oral administration is atablet.

Free base and acid addition salt forms of the compounds of formula 1exhibit the same type of activity. Examples of pharmaceuticallyacceptable acid addition salt forms are the hydrochloride, hydrogenoxalate and oxalate forms.

Specific examples of daily doses, at which satisfactory results areobtained, are as follows, viz.

(i) 4J2-Hydroxy-3-(2- 0.01 to 10 mg/kg hydroxymethyl2propylamino)propoxyIoxindole animal body weight administered i.\.:

pivaloyloxymethyl-2- propylamino lpropoxy oxindole4-13-(2-Hydroxymethyl- 2 propylamino )-2- pivaloyloxypropoxy1- animalbody weight administered i.v.;

0.01 m 10 mg/kg animal body weight administered iv oxindole Examples ofthe present invention will now be described in more detail, wherein alltemperatures referred to are in degrees Centigrade.

EXAMPLE l 4-[2-Hydroxy-3-(2-hydroxymethyl-Z-propylamino)-propoxyloxindole (process b)) A solution of 1.5 g of2-methyl-2-[2-hydroxy-3-(4- oxindolyloxy)propylamino]propionic acidethyl ester in 100 cc of absolute tetrahydrofuran is added dropwise to400 mg of lithium borohydride and 30 cc of absolute tetrahydrofuranwhile stirring and in an atmosphere of nitrogen, and the mixture isheated to 80 for 5 hours. The mixture is subsequently decomposed withwater while cooling, the undissolved material is filtered off and thefiltrate is concentrated by evaporation at reduced pressure. Theresulting crude title compound is recrystallized from methanol/ethylacetate. M.P. l53l56.

The 2-methyl-2-[2-hydr0xy-3-(4-oxindolyloxy)- propylamino]propionic acidethyl ester, used as starting material, is produced as follows:

3 g of 4-(2,3-epoxypropoxy)oxindole, 10.4 g of a-aminoisobutyric acidethyl ester and 40 cc of tetrahydrofuran are heated to the boil for 2days while stirring. The hot solution is filtered and allowed tocrystallize.

The compound crystallizes from ether. M.P. l58-160.

EXAMPLEZ 4-[2-Hydroxy-3-(2-hydroxymethyl-Z-propylamino)-propoxy]oxindole (process a)) 5 g of 4-(2,3-epoxypropoxy)oxindole, 3.3 gof 2-amino-2-methyl-l-propanol and 50 cc of dioxane are heated to theboil at reflux for 16 hours. The reaction mixture is evaporated todryness at reduced pressure, the residue is extracted between ethylacetate and l N tartaric acid solution, the tartaric acid phases aremade alkaline with 2 N caustic soda solution while cooling andextraction is effected with methylene chloride. The evaporation residueof the methylene chloride phase which has been dried over magnesiumsulfate yields the title compound. M.P. 155-l58 (ethyl acetate).

In analogous manner to that described in Examples 1 and 2, the compound7-[2-hydroxy-3-(2- hydroxymethyl-2-propylamino)propoxy]oxindole isproduced.

EXAMPLE 3 4-[2-Pivaloyloxy-3-( 2-pivaloyloxymethyl-2-propylamino)propoxy]oxindole (process c)) 1.5 g of4-[2-hydroxy-3-(2-hydroxymethyl-2- propylamino)propoxy]oxindole arestirred at room temperature for 2 /2 hours together with 10.4 g ofpivalic acid and 2.85 g of pivalic acid anhydride. The mixture is pouredon ice and is made alkaline with a 10 percent aqueous ammonia solution,extraction is effected with ethyl acetate, the extracts are dried overmagnesium sulfate and the solvent is evaporated at reduced pressure. Theresulting compound is converted into its hydrogen maleate, which isrecrystallized from ethanol. M.P. l58160.

EXAMPLE 4 4-[2-Hydroxy-3-(2-pivaloyloxymethyl-2-propylamino)propoxyloxindole (compound A) and4-[3-(2-hydroxymethyl-2-propylamino)-2 pivaloyloxypropoxyloxindole(compound B) (process 1.5 g of 4-[2-hydroxy-3-(2-hydroxymethyl-2-propylamino)propoxyloxindole are dissolved in 10.4 g of pivalic acid,and 0.95 g of pivalic acid anhydride are subsequently added at roomtemperature within 20 minutes. The reaction mixture is stirred at roomtemperature for 1 hour and is then worked up as described in Example 3.The resulting oily crude product consists of the compounds A and B, aswell as the diester (Example 3). The separation into the individualcomponents is effected by chromatography on 70 parts of silica gel withmethylene chloride and addition of l to 5 percent of methanol. Theresulting individual coml-methyl-4-[ 2-hydroxy-3-( 2-lauroyloxymethyl-2-propylamino)-propoxyloxindole,

4 {312-(cyclopropylcarbonyloxymethyl)-2-propylamino1-2-hydroxy-propoxy}oxindole,

4-[2-cyclohexylcarbonyloxy-3-(9- hydroxynonylamino)-propoxy]oxindole,

4-{2-hydroxy-3-[9-(Z-thenoyloxy)-nonylamino]- propoxyl oxindole,

4-{ 3-[9-( Z-furoyloxy )nonylaminol-2-hydroxypropoxy}oxindole,

4-[2-hydroxy-3-(9-nicotinoyloxynonylamino)- propoxyloxindole,

4-{2-hydroxy-3-[9-(4- tetrahydropyranylcarbonyloxy )nonylaminopropoxy}oxindole,

4-[2-benzoyloxy-3-(Z-hydroxymethyl-Z- propylamino)-propoxy]oxindole,

4-[3-(Z-hydroxymethyl-2-propylamino)-2-(7phenyloenanthoyloxy)-propoxy]oxindole,

4-[ 3-( 2-hydroxymethyl-2-propylamino )-2-phenylacetoxypropoxyloxindole,

4-{ 2-cinnamoyloxy-3-( 2-hydroxymethyl-2- propylamino)-propoxy]oxindole,

4- 2-(2-chlorobenzoyloxy )-3-( 2-hydroxymethyl2-propylamino)-propoxy]oxindole,

4 [2-(2-fluorobenzoyloxy)-3-(2-hydroxymethyl-2-propylamino)-propoxy]oxindole,

4-{2-[(Z-bromophenyl)acetoxy]-3-(2- hydroxyrnethyl-2-propylamino)-propoxy}oxindole,

4-{3-(2-hydroxymethyl2-propylamino)-2-(4-methoxycinnamoyloxy)-propoxyloxindole and 4- 3-(2-hydroxymethyl-Z-propylamino)-2-[ 7-( 4-methylphenyl)oenanthoyloxy]-propoxy}oxindole.

What is claimed is:

l. A compound of the formula:

OR R

wherein the aminopropoxy side chain is in the 4 or 7 45 position of theoxindole structure,

R is hydrogen or alkyl of l to 4 carbon atoms, both n is an integer from1 to 8, and R and R which are the same or different, are each hydrogenor the group COR wherein 5 R is alkyl of l to 12 carbon atoms;cycloalkyl of 3 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atomssubstituted by alkyl of l to 4 carbon atoms; thienyl; furyl; pyridyl; ortetrahydropyranyl', phenyl; phenyalkyl of 7 to 12 carbon atoms; styryl;or phenyl, phenylalkyl of 7 to 12 carbon atoms or styryl monosubstituted, on the phenyl nucleus thereof, by fluorine, chlorine,bromine, alkyl of l to 4 carbon atoms or alkoxy of l to 4 carbon atoms,in free base or pharmaceutically acceptable acid addi- 15 tion saltform.

2. A compound of claim 1, wherein R, is hydrogen. 3. A compound of claim1, wherein the amino propoxy side chain is in the 4 position of theoxindole structure.

4. A compound of claim 1, wherein n is an integer from 1 to 3.

5. A compound of claim 1, wherein the aminopropoxy side chain is in the4 position of the oxindole structure, R is hydrogen, both groups R arethe same and are each alkyl of l to 4 carbon atoms, n is the integer l,and R and R which are the same or different, are each hydrogen or thegroup COR wherein R is alkyl of 3 to 6 carbon atoms.

6. The compound of claim 5, which is 4-[2-Hydroxy-3-(Z-hydroxymethyl-2-propylamino propoxy]oxindo1e. 7. The compound ofclaim 5, which is 4-[2-Pivaloyloxy-3-(Z-pivaloyloxymethyl-Z-propylamino)propoxy]oxindole. 8. The compound of claim 5, which is 4-[2-HydroXy-3-( 2-pivaloyloxymethyl-2- propylamino)propoxy1oxindole.

9. The compound of claim 5 which is 4-[ 3-(Z-Hydroxymethyl-Z-propylamino )-2- pivaloyloxypropoxy]oxindole.

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1, wherein R1 ishydrogen.
 3. A compound of claim 1, wherein the aminopropoxy side chainis in the 4 position of the oxindole structure.
 4. A compound of claim1, wherein n is an integer from 1 to
 3. 5. A compound of claim 1,wherein the aminopropoxy side chain is in the 4 position of the oxindolestructure, R1 is hydrogen, both groups R2 are the same and are eachalkyl of 1 to 4 carbon atoms, n is the integer 1, and R3 and R4, whichare the same or different, are each hydrogen or the group -COR5, whereinR5 is alkyl of 3 to 6 carbon atoms.
 6. The compound of claim 5, which is4-(2-Hydroxy-3-(2-hydroxymethyl-2-propylamino)propoxy)oxindole.
 7. Thecompound of claim 5, which is4-(2-Pivaloyloxy-3-(2-pivaloyloxymethyl-2-propylamino)propoxy)oxindole.8. The compound of claim 5, which is4-(2-Hydroxy-3-(2-pivaloyloxymethyl-2-propylamino)propoxy)oxindole. 9.The compound of claim 5 which is4-(3-(2-Hydroxymethyl-2-propylamino)-2-pivaloyloxypropoxy)oxindole.